The publications and other materials used herein to illuminate the background of the invention, and in particular, cases to provide additional details representing the practice, are incorporated by reference.
Fibroproliferative vasculopathy includes restenosis following coronary bypass surgery and PTCA (percutaneous transluminal coronary angioplasty), allograft arteriosclerosis in chronic allograft rejection, diabetic angiopathy and all forms of common arteriosclerosis.
Vascular intimal dysplasia and remodelling are characteristic features of reinjury following balloon angioplasty, coronary bypass surgery (Holmes et al. 1984; Holmes et al. 1988) and in chronic allograft rejection (Lemstrom and Koskinen, 1997; Hayry et al. 1993). The initial response to vascular injury is inflammatory and involves attraction of lymphocytes, macrophages and thrombocytes to the site of injury and secretion of cytokines, eicosanoids and growth factors (Ross 1993). Under the influence of growth factors and cytokines, smooth muscle cells (SMC) proliferate and migrate from the media to the intima and contribute to intimal hyperplasia and stenosis. The key mediators of SMC proliferation and migration are IL-1, TNF.alpha., PDGF, IGF1, bFGF, EGF, TGF.beta. and VEGF (Asahara et al. 1995; Bornfeldt et al. 1994; Ferns et al. 1991; Libby and Galis 1995, Galis et al. 1995; Gronwald et al. 1989; Hancock et al. 1994; Hayry et al. 1995; Lindner and Reidny 1991; Myllarnemi et al. 1997; Nabel et al. 1993; Shi et al. 1996; Tanaka et al. 1996) and the matrix metalloproteinases in SMC locomotion through the extracellular matrix (Bendeck et al. 1996; Galis et al. 1995). In view of the central role of SMC proliferation, therapeutic strategies designed to prevent stenosis have attempted to suppress SMC proliferation by blocking the production and action of growth factors and cytokines with receptor antagonists or antisense oligonucleotides directed against cell cycle regulatory molecules (Hayry et al. 1995; Myllarniemi et al. 1997; Sirois et al. 1997; Wrighton et al. 1996). One important inhibitor of mitogenic signalling is somatostatin (SST) (Grant et al. 1994; Hong et al. 1993; Yumi et al. 1997).
The neurohormone SST is produced widely in the body and acts both systemically via the circulation and locally to inhibit cell proliferation as well as the secretion of various hormones, growth factors and neurotransmitter substances, SST and its metabolically more stable synthetic analogs, such as SMS201-995 (octreotide) and BIM23014 (lanreotide, angiopeptin), exert a number of vascular effects such as vasoconstriction in the gut and inhibition of angiogenesis. The actions of SST are mediated by a family of five heptahelical G protein coupled receptors termed SSTR1-5. All five SSTRs are functionally coupled to inhibition of adenylyl cyclase. Some of the receptor isotypes also modulate other effectors such as phosphotyrosine phosphatase, K.sup.- and voltage-dependent Ca.sup.2+ ion channels, a Na.sup.+ /H.sup.+ exchanger, phospholipase A.sub.2 and MAP kinase (MAPK). Based on structural similarity and the ability to react with octapeptide and hexapeptide SST analogs, the SST receptor family can be subdivided into two categories: the SSTR2,3,5 category with high affinity to these analogs and the SSTR1,4 category with low affinity to these compounds (see Table).
In experiments using arterial, venous, and vascular transplant models in various animal species, the administration of octreotide or lanreotide prevents the formation of dysplastic lesions (Foegh et al. 1994; Foegh and Ramwell 1995; Grant et al. 1994; Hong et al. 1993; Yumi et al. 1997; Hayry et al. 1993). These results however, have been inconsistent in different experimental models. In randomized placebo controlled clinical traits, lanreotide in some studies has been shown to prevent restenosis after percutaneous transluminal angioplasty as quantitated by angiography or as clinical events (Eriksen et al. 1995; Emanuelsson et al. 1995), whereas the same therapeutic response has not been achieved with octreotide (von Essen et al. 1997). Differences in the binding specificity of the SST analogs for the five SSTRs as well as the dose and duration of administration of SST analogs may contribute in part to the inconsistent results obtained in these studies. For instance, octreotide and lanreotide both bind with high affinity to SSTR2 and SSTR5 but display species-dependent-variability in binding to SSTR3; octreotide binds well to human SSTR3 but shows only moderate affinity for the rodent receptor, whereas the opposite is the case for lanreotide. To optimize the vasculoprotective effect of SST, the ideal approach would be to characterize the pattern of expression of SSTRs in the vascular wall after trauma, and to target the subtypes involved with appropiate agonists. Towards this objective, we have determined the time course of expression of mRNA for SSTR1-5 in rat aorta after endothelial denudation (balloon injury) by reverse transcription polymerase chain reaction (RT-PCR) and localized the reseptors directly by immunocytochemistry with rabbit polyclonal antibodies to receptor subtype specific peptides.